Compositions, systems, kits, and methods of administering rapamycin analogs with paclitaxel using medical devices

Abstract

A system and compositions including zotarolimus and paclitaxel are disclosed, as well as methods of delivery, wherein the drugs have effects that complement each other. Medical devices are disclosed which include supporting structures that include at least one pharmaceutically acceptable carrier or excipient, which carrier or excipient can include one or more therapeutic agents or substances, with the carrier including at least one coating on the surface thereof, and the coating associated with the therapeutic substances, such as, for example, drugs. Supporting structures for the medical devices that are suitable for use in this invention include, but are not limited to, coronary stents, peripheral stents, catheters, arterio-venous grafts, by-pass grafts, and drug delivery balloons used in the vasculature. These compositions and systems can be used in combination with other drugs, including anti-proliferative agents, anti-platelet agents, anti-inflammatory agents, anti-thrombotic agents, cytotoxic drugs, agents that inhibit cytokine or chemokine binding, cell de-differentiation inhibitors, anti-lipaedemic agents, matrix metalloproteinase inhibitors, cytostatic drugs, or combinations of these and other drugs.

1. A system for providing controlled release delivery of drugs for inhibiting neointimal hyperplasia in a blood vessel, comprising:
 a composition including a plurality of therapeutic substances including zotarolimus or salts or prodrugs thereof; and paclitaxel or salts or prodrugs thereof; 
 wherein the activities of said therapeutic agent(s) are complementary; 
 wherein the prodrug of paclitaxel is an ester formed from paclitaxel and a group selected from the group consisting of acetyl, proprionyl, pivaloyl, pivaloyloxymethyl, acetoxymethyl, phthalidyl, methoxymethyl, indanyl, natural and non-natural amino acids; 
 wherein the prodrug of zotarolimus is an ester formed from zotarolimus and a group selected from the group consisting of acetyl, proprionyl, pivaloyl, pivaloyloxymethyl, acetoxymethyl, phthalidyl, methoxymethyl, indanyl, and natural and non-natural amino acids; or is of the following formula: 
 
       
         
           
           
               
               
           
         
         wherein
   R=R 1 C(O)R 2 R 3  or R 1 C(S)R 2 R 3    
 
         where
 R 1 =O or S; 
 R 2 =nothing, O, N, S, alkyl, alkenyl, alkynyl, heterocycles, or aryl; 
 R 3 =nothing, alkyl, alkenyl, alkynyl, heterocycles, or aryl,
 wherein alkyl, alkenyl, alkynyl, heterocycles, aryl groups are substituted or unsubstituted; 
 
 
         and 
         wherein the composition is associated with a stent, 
         wherein the ratio of zotarolimus:paclitaxel by weight is 10:7≦r≦10:0.1, 
         wherein the loading of zotarolimus ranges from about 1 μg/mm to about 100 μg/mm of the stent and the loading of paclitaxel is 1 μg/mm of the stent. 
       
     
     
       2. The system of  claim 1 , further comprising a third drug, wherein zotarolimus or paclitaxel complement the activity of the third drug. 
     
     
       3. The system of  claim 1 , wherein the stent is further associated with at least one coating on a surface. 
     
     
       4. The system of  claim 3 , wherein the coating is associated with the composition. 
     
     
       5. The system of  claim 1 , wherein zotarolimus and paclitaxel are present in a ratio, r, that exerts an additive effect. 
     
     
       6. The system of  claim 1 , wherein r=10:1. 
     
     
       7. The system of  claim 6 , wherein the loading of zotarolimus is 10 μg/mm of the stent, and the loading of paclitaxel is 1μg/mm of the stent. 
     
     
       8. The system of  claim 1 , further comprising a third therapeutic substance. 
     
     
       9. The system of  claim 8 , wherein the third therapeutic substance is selected from the group consisting of anti-proliferative agents, anti-platelet agents, anti -inflammatory agents, anti-thrombotic agents and thrombolytic agents. 
     
     
       10. The system of  claim 9 , wherein the anti-inflammatory agent is one selected from the group consisting of steroidal and non-steroidal anti-inflammatory agents including dexamethasone, hydrocortisone, estradiol, acetaminophen, ibuprofen, naproxen, fluticasone, clobetasol, adalimumab, triamcinolone, mometasone, and sulindac. 
     
     
       11. The system of  claim 9 , wherein the third therapeutic substance comprises an antibody. 
     
     
       12. The system of  claim 3 , wherein the coating is polymeric. 
     
     
       13. A method of treating a subject, comprising placing the system of  claim 1 . 
     
     
       14. A kit, comprising the system of  claim 1 . 
     
     
       15. A drug delivery system, comprising
 a stent comprising a coating on a surface, the coating comprising a therapeutic composition comprising zotarolimus, prodrugs or salts thereof and paclitaxel, prodrugs or salts thereof, 
 wherein neointimal hyperplasia is reduced when the system is implanted in a lumen of a blood vessel of a subject when compared to a control system; 
 wherein neointimal hyperplasia is reduced by ≧10% when compared to the control system; 
 wherein the ratio, r, of zotarolimus:paclitaxel by weight is 10:7≦r≦10: 0.1, 
 wherein the loading of zotarolimus ranges from about 1 μg/mm to about 100 μg/mm of the stent and the loading of paclitaxel is 1 μg/mm of the stent; and 
 wherein the prodrug of paclitaxel is an ester formed from paclitaxel and a group selected from the group consisting of acetyl, proprionyl, pivaloyl, pivaloyloxymethyl, acetoxymethyl, phthalidyl, methoxymethyl, indanyl, natural and non-natural amino acids; and 
 wherein the prodrug of zotarolimus is an ester formed from zotarolimus and a group selected from the group consisting of acetyl, proprionyl, pivaloyl, pivaloyloxymethyl, acetoxymethyl, phthalidyl, methoxymethyl, indanyl, and natural and non-natural amino acids; or is of the following formula: 
 
       
         
           
           
               
               
           
         
         wherein
   R=R 1 C(O)R 2 R 3  or R 1 C(S)R 2 R 3    
 
         where
 R 1 =O or S; 
 R 2 =nothing, O, N, S, alkyl, alkenyl, alkynyl, heterocycles, or aryl; 
 R 3 =nothing, alkyl, alkenyl, alkynyl, heterocycles, or aryl,
 wherein alkyl, alkenyl, alkynyl, heterocycles, aryl groups are substituted or unsubstituted. 
 
 
       
     
     
       16. The system of  claim 15 , wherein r=10:1. 
     
     
       17. The system of  claim 15 , wherein the loading of zotarolimus is 10 μg/mm of the stent, and the loading of paclitaxel is 1 μg/mm of the stent. 
     
     
       18. A system for providing controlled release delivery of drugs for treating or inhibiting neointimal hyperplasia in a blood vessel, comprising:
 a stent, the stent associated with at least one coating that comprises zotarolimus, salts or prodrug thereof and paclitaxel, salts or prodrug thereof; 
 wherein the ratio of zotarolimus:paclitaxel by weight is 10:7≦r≦10:0.1, 
 wherein the loading of zotarolimus ranges from about 1 μg/mm to about 100 μg/mm of the stent and the loading of paclitaxel is 1 μg/mm of the stent; 
 wherein zotarolimus complements paclitaxel activity, and paclitaxel complements zotarolimus activity; and 
 wherein the prodrug of paclitaxel is an ester formed from paclitaxel and a group selected from the group consisting of acetyl, proprionyl, pivaloyl, pivaloyloxymethyl, acetoxymethyl, phthalidyl, methoxymethyl, indanyl, natural and non-natural amino acids; and 
 wherein the prodrug of zotarolimus is an ester formed from zotarolimus and a group selected from the group consisting of acetyl, proprionyl, pivaloyl, pivaloyloxymethyl, acetoxymethyl, phthalidyl, methoxymethyl, indanyl, and natural and non-natural amino acids; or is of the following formula: 
 
       
         
           
           
               
               
           
         
         wherein
   R=R 1 C(O)R 2 R 3  or R 1 C(S)R 2 R 3    
 
         where
 R 1 =O or S; 
 R 2 =nothing, O, N, S, alkyl, alkenyl, alkynyl, heterocycles, or aryl; 
 R 3 =nothing, alkyl, alkenyl, alkynyl, heterocycles, or aryl,
 wherein alkyl, alkenyl, alkynyl, heterocycles, aryl groups are substituted or unsubstituted. 
 
 
       
     
     
       19. The system of  claim 18 , wherein r=10:1. 
     
     
       20. The system of  claim 19 , wherein the loading of zotarolimus is 10 μg/mm of the stent, and the loading of paclitaxel is 1μg/mm of the stent. 
     
     
       21. The system of  claim 12 , wherein the polymeric coating comprises poly(MPC w :LAM x :HPMA y :TSMA z ),
 wherein w, x, y, and z represent the molar ratios of monomers, 
 MPC represents 2-methacryoyloxyethylphosphorylcholine, 
 LMA represents lauryl methacrylate, 
 HPMA represents 2-hydroxylpropyl methacrylate, and 
 TSMA represents 3-trimethoxysilylpropyl methacrylate. 
 
     
     
       22. The system of  claim 1 , wherein the composition further comprising a polymer, wherein the ratio of total drug to polymer is 90:10 or lower. 
     
     
       23. The system of  claim 1 , wherein the composition further comprising a polymer, wherein the ratio of total drug to polymer is 40:60 or lower. 
     
     
       24. The system of  claim 15 , wherein the coating further comprising a polymer, wherein the ratio of total drug to polymer is 90:10 or lower. 
     
     
       25. The system of  claim 15 , wherein the coating further comprising a polymer, wherein the ratio of total drug to polymer is 40:60 or lower.